This invention relates to a novel process for the production of 4-alkylpiperazinylsulfonylphenyl- and 4-alkylpiperazinylsulfonyl pyridinyldihydropyrazolo[4,3-d]pyrimidin-7-one derivatives, and, in particular, the anti-impotence drug, sildenafil and analogues thereof.
Sildenafil (5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), 
is the active ingredient in Viagra(trademark). The compound, which was originally disclosed in European patent application EP 463 756, has been found to be particularly useful in the treatment of inter alia male erectile dysfunction (see international patent application WO 94/28902).
Multi-step syntheses for the production of sildenafil are described in EP 463 756. An improved process for its production is described in a later application (European patent application EP 812 845), the final step of which involves an internal cyclisation under basic, neutral or acidic conditions.
We have now found that sildenafil and analogues thereof may be made via a novel process, as described hereinafter, which process has advantages over the processes described in the above-mentioned prior art documents.
According to a first aspect of the invention, there is provided a process for the production of compounds of general formula I: 
wherein
A represents CH or N;
R1 represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b and SO2NR11aR11b;
R2 and R4 independently represent lower alkyl;
R3 represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R5, R6, R7, R8, R9, R11a and R11b independently represent H or lower alkyl;
R10a and R10b either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl,
which process comprises the dehydrogenation of a compound of general formula II, 
wherein A, R1, R2, R3 and R4 are as defined above,
which process is referred to hereinafter as xe2x80x9cthe process of the inventionxe2x80x9d.
According to a second aspect of the invention, there is provided a process for the production of compounds of general formula I: 
wherein
A represents CH or N;
R1 represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b and SO2NR11aR11b;
R2 and R4 independently represent lower alkyl;
R3 represents lower alkyl, which alkyl group is optionally interrupted by oxygen; Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R5, R6, R7, R8, R9, R11a and R11b independently represent H or lower alkyl;
R10a and R10b either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl;
with the proviso that the compound of formula I is not sildenafil;
which process comprises the dehydrogenation of a compound of general formula II, 
wherein A, R1, R2, R3 and R4 are as defined above,
which process is referred to hereinafter as xe2x80x9cthe process of the inventionxe2x80x9d.
According to a third aspect of the invention, there is provided a process for the production of compounds of general formula I: 
wherein
A represents CH;
R1 represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b and SO2NR11aR11b;
R2 and R4 independently represent lower alkyl;
R3 represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R5, R6, R7, R8, R9, R11a and R11b independently represent H or lower alkyl;
R10a and R10b either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl;
with the proviso that the compound of formula I is not sildenafil;
which process comprises the dehydrogenation of a compound of general formula II, 
wherein A, R1, R2, R3 and R4 are as defined above,
which process is referred to hereinafter as xe2x80x9cthe process of the inventionxe2x80x9d.
According to a fourth aspect of the invention, there is provided a process for the production of compounds of general formula I: 
wherein
A represents N;
R1 represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b and SO2NR11aR11b;
R2 and R4 independently represent lower alkyl;
R3 represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R5, R6, R7, R8, R9, R11a and R11b independently represent H or lower alkyl;
R10a and R10b either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl,
which process comprises the dehydrogenation of a compound of general formula II, 
wherein A, R1, R2, R3 and R4 are as defined above,
which process is referred to hereinafter as xe2x80x9cthe process of the inventionxe2x80x9d.
The compounds of general formulae I and II can be represented by the formulae IA and IB and IIA and IIB as detailed hereinafter. The novel process according to the present invention includes compounds of the formulae IA, IB, IIA and IIB. 
The term xe2x80x9carylxe2x80x9d, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl and the like.
Het groups may be fully saturated, partly unsaturated, wholly aromatic, partly aromatic and/or bicyclic in character. Het groups that may be mentioned include groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl, piperazinyl, thienyl and furanyl.
The point of attachment of any Het group may be via any atom in the ring system including (where appropriate) a heteroatom. Het groups may also be present in the N- or S-oxidised form.
The term xe2x80x9clower alkylxe2x80x9d (which includes the alkyl part of alkylHet and alkylaryl groups), when used herein, includes C1-6 alkyl (e.g. C1-4 alkyl). Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, and/or be substituted by one or more halo atoms.
As defined herein, the term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo.
Compounds of formulae I, IA and IB may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. The process of the invention thus also relates to the formation of stereoisomers of compounds of formulae I, IA and IB and mixtures thereof. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, crystallisation, chromatography over silica or, for example, via classical resolution with a homochiral acid salt). The formation of all stereoisomers is included within the scope of the invention.
Preferred compounds of formulae I, IA and IB include those in which:
R1 represents C1-4 alkyl, which alkyl group is optionally interrupted by an oxygen atom, and/or is optionally terminated by a Het group (such as a pyridinyl group);
R2 represents C1-4 alkyl;
R3 represents C1-5 alkyl, which alkyl group is optionally interrupted by an oxygen atom;
R4 represents C1-3 alkyl.
More preferred compounds of formulae I, IA and IB include those in which:
R1 represents linear C1-3 alkyl, which alkyl group is optionally interrupted by an oxygen atom, or is optionally terminated by a 2-pyridinyl group (e.g. to form a 2-pyridinylmethyl group);
R2 represents linear C2-3 alkyl;
R3 represents linear or branched C2-4 alkyl, which alkyl group is optionally interrupted by an oxygen atom;
R4 represents C1-2 alkyl.
Particularly preferred compounds that may be formed in the process of the invention include sildenafil, and the following four compounds: 
The process of the invention may be carried out in accordance with reaction conditions known to those skilled in the art in the presence of a suitable dehydrogenation agent (for example: a catalyst such as palladium on carbon (e.g. 5% Pd/C or 10% Pd/C), preferably in the presence of a hydrogen acceptor such as cyclohexene or maleic acid and/or an acid such as trifluoroacetic acid, HCl or H2SO4; a high oxidation potential quinone such as 2,3,5,6-tetrachloro-1,4-benzoquinone or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; (atmospheric) oxygen; MnO2; or triphenylmethanol in trifluoroacetic acid). A hydrogen sulfite salt such as sodium hydrogen sulfite may also serve to effect removal of hydrogen from the compound of general formula II (IIA and IIB). Preferred dehydrogenation agents include catalysts such as 5% Pd/C or 10% Pd/C, preferably in the presence of a hydrogen acceptor such as cyclohexene or maleic acid and/or an acid such as trifluoroacetic acid. The reaction may be carried out in an appropriate organic solvent system, which solvent system should not significantly react chemically with, or significantly give rise to stereochemical changes in, the reactants or product once formed, or significantly give rise to other side reactions. Preferred solvent systems include aromatic hydrocarbons, such toluene and xylene.
The process of the invention may be carried at above room temperature (e.g. between 125 and 250xc2x0 C., preferably 150 and 230xc2x0 C., more preferably 175 and 220xc2x0 C., depending upon the solvent system that is employed), and/or at high pressure (e.g. between 13.8 and 68.9 kPa (2 and 10 psi), preferably between 27.6 and 41.4 kPa (4 and 6 psi), such as around 34.5 kPa (5 psi)), and/or, optionally, in an inert atmosphere (i.e. in the presence of an inert gas, such as nitrogen or argon).
Appropriate reaction times and reaction temperatures depend upon the solvent system that is employed, as well as the compound that is to be formed, but these may be determined routinely by the skilled person.
We have found that compounds of general formula II (and IIA and IIB) hereinbefore defined may be prepared, advantageously, by way of reaction of an aldehyde compound of formula III, 
wherein A, R3 and R4 are as hereinbefore defined, with a compound of formula IV, 
wherein R1 and R2 are as hereinbefore defined.
This condensation/cyclisation reaction may be carried out at above room temperature (e.g. at around the reflux temperature of the solvent that is employed) in the presence of a suitable solvent (for example: an aromatic hydrocarbon, such as toluene or xylene; chlorobenzene; or diphenylether). This reaction may also be carried out under pressure at a higher temperature than the reflux temperature of the relevant solvent that is employed.
The compounds of general formula IV may be represented by the formulae IVA and IVB. 
Advantageously, we have found that compounds of general formula I (and IA and IB) hereinbefore defined may be formed directly from corresponding compounds of formula III in a xe2x80x9cone potxe2x80x9d procedure, in which a compound of formula III is reacted with a compound of general formula IV at high temperature, and under pressure, using an appropriate reaction vessel. Following this reaction, the dehydrogenation agent(s) may be added to the reaction vessel and the dehydrogenation reaction performed on the intermediate compound of formula IIA or IIB, formed in situ, under similar conditions to those described hereinbefore.
Without wishing to be bound by a particular theory, it is believed that the reaction between compounds III and IV proceeds via either an imine intermediate of general structure: 
or an aminol intermediateof general structure: 
to form the compound of general formula II as hereinbefore defined.
Compounds of formula III may be prepared by known techniques. For example:
(a) Compounds of formula III in which A represents CH may be prepared from readily available starting materials of formula V, 
wherein R3 is as hereinbefore defined, in analogous fashion to the techniques described in German patent application DE 24 44 720, the disclosure in which document is hereby incorporated by reference.
(b) Compounds of formula III in which A represents CH may alternatively be prepared by oxidation of a compound of formula VI, 
wherein R3 and R4 are as hereinbefore defined, in the presence of a suitable oxidising agent (for example: MnO2; tetra-n-propylammonium perruthenate (catalytic) combined with 4-methylmorpholine N-oxide; or oxalyl chloride combined with dimethylsulfoxide and triethylamine) and an appropriate organic solvent (for example: acetone; dichloromethane; an aromatic hydrocarbon (e.g. toluene or xylene); chlorobenzene; or an aliphatic hydrocarbon (e.g. pentane, hexane or petroleum ether)).
Compounds of formula VI may be prepared directly by reduction of a corresponding carboxylic acid of formula VII, 
wherein R3 and R4 are as hereinbefore defined, under conditions known to those skilled in the art (for example, using: LiAlH4; borane; NaBH4, added after activation with iodine; diisobutylaluminium hydride; or NaBH4 combined with an acid activating agent (e.g. carbonyldiimidazole, thionyl chloride or methyl chloroformate)). Compounds of formula VII may be prepared according to, or by analogy with, methods described in European patent application EP 812 845.
However, in order to prepare compounds of formula VI more conveniently, we prefer that a compound of formula VII is first esterified under standard conditions to form a compound of formula VIIIA, 
wherein Ra represents lower alkyl (e.g. C1-6, such as linear or branched C1-4, alkyl (e.g. methyl, ethyl or n- or i-propyl)) and R3 and R4 are as hereinbefore defined, followed by reduction of the ester using techniques known to those skilled in the art (e.g. catalytic hydrogenation or, more preferably, chemical reduction). Appropriate chemical reducing agents include, for example, Red-AI(copyright), DIBAL-H or LiAlH4. When the reducing agent is, for example, Red-AI(copyright), the reduction may be carried out in the presence of a suitable organic solvent (for example: an aromatic hydrocarbon (e.g. toluene or xylene); chlorobenzene; an aliphatic hydrocarbon (e.g. pentane, hexane or petroleum ether); THF; diisopropyl ether; or dichloromethane), under a positive pressure of inert gas (e.g. nitrogen or argon), for example at or around room temperature.
(c) Compounds of formula III in which A represents N may be prepared by reduction of a corresponding compound of formula VIIIB, 
wherein Ra, R3 and R4 are as hereinbefore defined, in the presence of a suitable reducing agent, for example, Red-AI(copyright) or DIBAL-H. When the reducing agent is DIBAL-H, this reduction may be performed, for example, at low temperature (e.g. at xe2x88x9278xc2x0 C.) in the presence of an appropriate solvent (for example: an aromatic hydrocarbon (e.g. toluene or xylene); chlorobenzene; an aliphatic hydrocarbon (e.g. pentane, hexane or petroleum ether); THF; diisopropyl ether; or dichloromethane).
Preferred compounds of formula III include those in which A represents N.
Compounds of formula VIIIB may be prepared in accordance with the methods detailed in the preparation section herein and by known techniques. For example, compounds of formula VIIIB may be prepared according to or by analogy with the procedures described in WO 99/54333 (in particular the procedures described in Preparations 18 and 19 of that document), the disclosures in which document are hereby incorporated by reference.
Compounds of formulae IV and V, and derivatives thereof, when not commercially available or not subsequently described, may be obtained by conventional synthetic procedures or by analogy with the processes described herein, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Compounds may be isolated from reaction mixtures using known techniques.
Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic, group(s) in compounds defined herein may be converted to other substituents using techniques well known to those skilled in the art. For example, amino may be converted to amido, amido may be hydrolysed to amino, hydroxy may be converted to alkoxy, alkoxy may be hydrolysed to hydroxy etc.
It will be appreciated by those skilled in the art that, in the processes described above, the functional groups of intermediate compounds may be, or may need to be, protected by protecting groups.
Functional groups which it is desirable to protect thus include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups). Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl, allyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by JWF McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd edition, TW Greene and PGM Wutz, Wiley-Interscience (1999).
Persons skilled in the art will appreciate that, in order to obtain compounds of formulae II, IIA or IIB in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
Certain intermediates that are employed in the processes described herein are novel. According to the invention there is further provided compounds of formulae IIA, IIB, III, VI and VIIIA as defined hereinbefore.
The process of the invention possesses the advantage that sildenafil and analogues thereof may be prepared from commercially-available starting materials in fewer steps than in processes described in the prior art, without concomitant losses in terms of yield of key intermediates and of final compounds. The process of the invention has the further advantage that sildenafil and analogues thereof may be made directly from readily available intermediates described herein (i.e. compounds of formula III) in a convenient one-pot procedure.
Further, the process of the invention may have the advantage that sildenafil and analogues thereof may be prepared in less time, more conveniently, and at a lower cost, than when prepared in processes described in the prior art.
The invention is illustrated, but in no way limited, by the following examples.
All 1H NMR spectra were recorded using a Varian Unity 300 MHz machine.